Method of administering natural female sex hormones

ABSTRACT

The invention relates to a novel method of administering the natural female sex hormones, 17 β- estradiol and progesterone, to achieve enhanced bioavailability thereof. The invention further relates to novel dosage forms of 17 β- estradiol and/or progesterone which are adapted for nasal administration, such as solutions, suspensions, gels and ointments. The dosage forms containing a combination of 17 β-estradiol and progesterone are particularly useful as contraceptives, while the dosage forms containing only one of the hormonal components find utility in the treatment of conditions such as menopause, menstrual disorders, etc., which are known to respond to administration of a natural or synthetic female hormone.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel method of administering thenatural female sex hormones, 17β-estradiol and progesterone, and tonovel dosage forms containing those compounds, singly or in combination,which are adapted for nasal administration.

2. Description of the Prior Art

17β-estradiol is the most potent natural estrogen found in human beingsand is the major secretory product of the ovary. It is readily oxidizedin the body to estrone, which in turn can be hydrated to estriol. Thesetransformations take place mainly in the liver, where there is freeinterconversion between estrone and estradiol. All three of thesenatural estrogens are excreted in the urine as glucuronides andsulfates, along with a host of related, minor products in water-solublecomplexes. It is widely known that, following oral administration ofmicronized 17β-estradiol (E₂), the incremental circulation estrogen isprincipally the less active species estrone (E₁), which reaches a peakconcentration many times greater than that of E₂. The conversion of E₂to E₁ and subsequently to other metabolites takes place duringabsorption from the intestine and passage through the liver. Thisextensive metabolism greatly limits the oral effectiveness of thenatural estrogens and their esters. Indeed, because of their limitedoral efficacy, 17β-estradiol and its esters are generally administeredby intramuscular injection.

Progesterone is the active natural progestin which occurs in the corpusluteum, placenta and adrenal cortex. It is not effective by mouthbecause of its rapid metabolism in the intestinal epithelium and in theliver, and is therefore only administered intramuscularly.

Because of their limited oral effectiveness, these natural female sexhormones have not found utility in oral contraceptives. Instead, onlyactive synthetic estrogens and progestins have been prepared and areused for contraceptive purposes. The synthetic derivatives have also inmany cases replaced the natural substances in the treatment ofmenopause, threatened abortion, etc. However, the synthetic derivativesare, generally speaking, much more likely to cause toxic side effectsthan are the relatively safe natural hormones.

SUMMARY OF THE INVENTION

In view of the foregoing, it is apparent that a serious need exists forthe improved delivery of the natural female sex hormones. Thus, it is anobject of the present invention to provide novel dosage forms and anovel method of administering 17β-estradiol and progesterone, separatelyor in combination, which will provide greatly enhanced bioavailabilityas compared to oral administration, while at the same time providingrelative ease of administration when compared to intramuscularinjection.

It is a further object of the present invention to provide a novelcontraceptive method and novel compositions for accomplishing same whichutilize the natural female sex hormones, 17β-estradiol and progesterone,and thus avoid the disadvantages inherent in the use of potentiallyunsafe synthetic estrogens and progestins.

It is yet a further object of the present invention to provide a novelmethod and novel dosage forms containing 17β-estradiol or progesteroneuseful in the treatment of conditions such as menopause, menstrualdisorders, etc. which are known to respond to administration of anatural or synthetic female sex hormone.

The foregoing objects are achieved by nasal administration of17β-estradiol (if desired, in the form of one of its estrogenicallyeffective esters) and/or progesterone. According to the invention, thesenatural female sex hormones are administered via a novel nasal dosageform, i.e., a solution, suspension, ointment or gel adapted for nasaladministration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a semi-logarithmic plot of mean blood levels of progesteroneafter intravenous (IV), nasal and intraduodenal/oral (ID) administrationof a dose of 50 μg of progesterone per rat.

FIG. 2 is a graph showing the area under the curve as a function of dosefor the intravenous (IV) and nasal routes of progesterone administration(50 μg, 100 μg and 150 μg dosage levels).

FIG. 3 is a semi-logarithmic plot of mean blood levels of totalunconjugated estrogens (TUE) following intravenous (IV), nasal andintraduodenal/oral (ID) administration of a dose of 10 μg of17β-estradiol per rat.

FIG. 4 is a semi-logarithmic plot of mean blood levels of estradiol (E₂)following intravenous (IV), nasal and intraduodenal/oral (ID)administration of a dose of 10 μg of 17β-estradiol per rat.

FIG. 5 is a semi-logarithmic plot of mean blood levels of estrone (E₁ )following intravenous (IV), nasal and intraduodenal/oral (ID)administration of a dose of 10 μg of 17β-estradiol per rat.

DETAILED DESCRIPTION OF THE INVENTION

The word "progesterone" as used herein means pregn-4-ene-3,20-dione,i.e., the compound of the formula ##STR1## and is intended to includeprogesterone derived from natural sources as well as that madesynthetically.

The word "17β-estradiol" as used herein is intended to encompass anypharmaceutically acceptable, estrogenically active form of17β-estradiol, i.e., estra-1,3,5(10)-triene-3,17β-diol itself, which hasthe formula ##STR2## and which may be extracted from natural sources ormade synthetically, or one of its 3- or 17-monoesters or 3,17-diesters.By way of illustration, suitable esters of 17β-estradiol for purposes ofthe present invention include 3-monoesters such as estradiol benzoateand estradiol 3-acetate; 17-monoesters such as estradiol cypionate,estradiol 17-propionate, estradiol 17-acetate, estradiol 17-heptanoate(estradiol enanthate), estradiol 17-undecanoate (estradiol undecylate)and estradiol 17-valerate; and 3,17-diesters such as estradioldipropionate and estradiol diacetate.

According to the present invention, it has surprisingly been found that17β-estradiol and progesterone can be administered nasally with resultsconsiderably superior to those obtained with oral administration. Thefollowing studies were undertaken to examine the bioavailability ofprogesterone and 17β-estradiol from nasal solution in comparison withthe bioavailability of these drugs when administered orally andintravenously.

Sprague-Dawley male rats, each weighing about 270 grams, were used inthe progesterone study. For nasal administration, the rats wereanesthetized using sodium pentobarbital (50 mg/kg) and the drug wasadministered to the nasal cavity by means of a micropipet at dosagelevels of 50 μg, 100 μg and 150 μg/rat of [4-¹⁴ C]-progesterone (˜8.5μCi/rat) in 0.1 ml of isotonic saline containing 1-2% Tween 80 as asolubilizing agent, according to the procedure described by Hirai et al,the 98th Annual Meeting of Pharmaceutical Society of Japan, Okayama,April 1978, except that the end of the tube leading from the esophagusto the nasal cavity was closed and the drug was administered to thenostrils which were then closed with an adhesive agent. For oral(intraduodenal) administration, the rats were anesthetized and theabdomen of each rat was opened through a midline incision and a 50μg/rat dose of the drug ([4-¹⁴ C]-progesterone in 0.1 ml isotonic salinewith 1-2% Tween 80) was injected directly through the duodenum. Forintravenous administration, the rats were anesthetized and the drug wasinjected through the femoral vein at dosage levels of 50 μg, 100 μg and150 μg/rat of [4-¹⁴ C]-progesterone in 0.1 ml of isotonic salinecontaining 1-2% Tween 80. Blood was sampled periodically from thefemoral aorta after IV and nasal administration, and from the tail veinafter ID administration. Blood levels of progesterone were determined bythin layer chromotography.

FIG. 1 shows the mean blood levels of progesterone for the studydescribed above after intravenous, nasal and oral administration of adose of 50 μg/rat, while Table I below summarizes the area under thecurve for the three routes of administration at the various doses.

                  TABLE I                                                         ______________________________________                                        AREA UNDER THE CURVE AFTER INTRAVENOUS,                                       NASAL AND INTRADUODENAL                                                       ADMINISTRATION OF PROGESTERONE IN RATS                                        Dose    AUC.sub.0.sup.∞ , ng.min/ml                                                                Nasal    ID                                        μg/rat                                                                              IV       Nasal   ID     IV     IV                                    ______________________________________                                         50     1612.2*  1659.0   19.0   1.029  0.012                                         ±80.8 ±109.2                                                                              ±4.6                                             100     3520.0   3599.0   --     1.022  --                                            ±491.0                                                                              ±621.4                                                    150     4480.2   4798.9   --     1.071  --                                            ±466.4                                                                              ±188.5                                                    ______________________________________                                         *mean ± SE(n = 4-6).                                                  

By using the two tailed t-test, it can be shown that the area under thecurve following intravenous and nasal administration at each dosage werenot significantly different, even at the 0.001 level. However, as can beseen from Table I, oral administration of 50 μg resulted inbioavailability equal to only 1.2% that of an equivalent dose givenintravenously. Also from Table I, it can be seen that the nasalbioavailability of progesterone at the 50 μg dosage level was 85.75times greater than the oral bioavailability.

It can also be seen from FIG. 1 that progesterone is very rapidlyabsorbed from the nasal mucosa; thus, at the 50 μg dosage level, thepeak plasma level was attained in less than 7 minutes after instillationof the nose drops.

FIG. 2 shows the area under the curve as a function of dose for theintravenous and nasal routes. As can be seen from FIG. 2, for both IVand nasal routes of administration the area under the curve (AUC) wasdirectly proportional to the dose administered.

The study described above indicates that progesterone is rapidlyabsorbed from the nasal mucosa into the systemic circulation withoutfirst pass metabolism. It is further apparent from this study that thebioavailability of progesterone when administered nasally is equivalentto the bioavailability of the drug where administered intravenously andvastly superior to its bioavailability by the oral route.

A study similar to that described above was undertaken to study thebioavailability of nasally administered 17β-estradiol vis-a-vis itsbioavailability via intravenous and oral routes. Sprague-Dawley malerats, each weighing approximately 270 grams, were given dosages of 5 μg,10 μg and 20 μg/rat of [6,7-³ H] 17β-estradiol in 0.1 ml isotonic salinecontaining 1% Tween 80 via the intravenous, nasal and intraduodenalroutes, according to the procedures described above with respect to theprogesterone study. Blood samples were taken periodically as describedin the progesterone study and assayed for estradiol (E₂), estrone (E₁)and total unconjugated estrogens (TUE).

FIGS. 3, 4 and 5 show typical plots of the mean blood levels of TUE, E₂and E₁ following intravenous, nasal and oral administration of 10 μg of17β-estradiol per rat. These figures clearly show that 17β-estradiol israpidly absorbed by the nasal mucosa.

Table II below shows the area under the curve for the three routes ofadministration at the various dosage levels of 17β-estradiol.

                  TABLE II                                                        ______________________________________                                        AREA UNDER THE CURVE AND BIOAVAILABILITY                                      OF TUE, E.sub.2 AND E.sub.1 FOR THE DIFFERENT ROUTES                          OF ADIMINISTRATION AT THE VARIOUS DOSES                                       DOSE   ROUTE OF        AUC.sub.0.sup.∞ , NG. MIN. ML.sup.-1             μG/RAT                                                                            ADMINISTRATION  TUE      E.sub.2                                                                             E.sub.1                                 ______________________________________                                         5     IV              555.5    290.8 53.4                                           NASAL           337.0    146.8 88.5                                                           (0.606)  (0.505)                                                                             (1.657)                                        ORAL            119.2    11.1  10.6                                                           (0.215)  (0.038)                                                                             (0.199)                                 10     IV              954.6    609.0 83.5                                           NASAL           761.2    415.2 173.1                                                          (0.797)  (0.682)                                                                             (2.073)                                        ORAL            314.2    19.1  16.8                                                           (0.329)  (0.031)                                                                             (0.201)                                 20     IV              1936.9   1062.6                                                                              164.4                                          NASAL           1777.2   891.8 354.0                                                          (0.918)  (0.839)                                                                             (2.153)                                        ORAL            786.9    53.4  42.4                                                           (0.406)  (0.050)                                                                             (0.258)                                 ______________________________________                                         () RATIO VS. IV                                                          

As can be seen from Table II, the TUE bioavailability after nasaladministration ranged from 60.6% to 91.8% that of the correspondingdoses given intravenously, while oral administration resulted in TUEbioavailability that ranged from only 21.5% to 40.6% that of thecorresponding doses given intravenously. Thus, nasal bioavailability ofTUE was from 2.26 to 2.83 times greater than oral bioavailability. Evenmore significantly, Table II further shows that the E₂ bioavailabilityafter nasal administration ranged from 50.5% to 83.9% that of thecorresponding doses given intravenously, while oral administrationresulted in E₂ bioavailabilities that ranged from only 3.1% to 5.0% thatof the corresponding doses given intravenously. Thus, nasalbioavailability of E₂ was from 13.23 to 21.74 times greater than oralbioavailability.

The studies described above indicate that progesterone and 17β-estradiol are rapidly absorbed from the nasal mucosa into systemicblood without extensive intestinal or first pass metabolism.

Progesterone and 17β-estradiol can be conveniently administered nasallyto warm-blooded animals by formulating them, singly or in combination,into a nasal dosage form comprising the selected natural female sexhormone(s) and a nontoxic pharmaceutically acceptable nasal carriertherefor. As indicated earlier, any pharmaceutically acceptable,estrogenically active form of 17β-estradiol can be employed in the nasalform, e.g., the diol itself or one of its esters. In a preferredembodiment of the invention, both progesterone and a suitable form of17β-estradiol are present in the nasal dosage form, which can beemployed in preventing conception, for example, by administration in acyclic manner analagous to that used for the oral contraceptives.

In another embodiment, the estrogenic component, i.e., one of thesuitable forms of 17β-estradiol, is present but progesterone is not;this type of composition may be used for any of a variety of conditionsfor which natural or synthetic estrogens have previously beenadministered, e.g., to control menopausal symptoms, hot flushes andlater osteoporosis; also in atropic vaginitis, and to relieve postpartumbreast engorgement, dysmenorrhea, amenorrhea, menorrhagia, and assubstitution therapy in ovarian dwarfism; also to control prostaticcarcinoma, and possibly also as a "morning-after" contraceptive. Also,the "estrogen only" nasal composition could be used in a sequentialcontraceptive regimen in which estrogen alone is to be administered fora part of the cycle.

In another embodiment of the present invention, progesterone is presentin the nasal dosage form, but the estrogenic component is not. This typeof composition may be used in the treatment of conditions for whichnatural or synthetic progestins have previously been used, e.g., inthreatened or habitual abortion, endometriosis and menstrual disorderssuch as dysmenorrhea and functional uterine bleeding, in inhibitingovulation and possibly as a "progestin only" continuously administeredcontraceptive (analogous to "minipill" type of oral contraceptives).

Suitable nontoxic pharmaceutically acceptable nasal carriers for use inthe compositions of the present invention will be apparent to thoseskilled in the art of nasal pharmaceutical formulations. For those notskilled in the art, reference is made to the text entitled "REMINGTON'SPHARMACEUTICAL SCIENCES", 4th edition, 1970. Obviously, the choice ofsuitable carriers will depend on the exact nature of the particularnasal dosage form desired, e.g. whether the active ingredient(s) is/areto be formulated into a nasal solution (for use as drops or as a spray),a nasal suspension, a nasal ointment or a nasal gel, as well as on theidentity of the active ingredient(s). Preferred nasal dosage forms aresolutions, suspensions and gels, which contain a major amount of water(preferably purified water) in addition to the active ingredient(s).Minor amounts of other ingredients such as pH adjusters (e.g., a basesuch as NaOH), emulsifiers or dispersing agents (e.g. polyoxyethylene 20sorbitan mono-oleate), buffering agents, preservatives, wetting agentsand jelling agents (e.g. methylcellulose) may also be present. Also, asustained release composition, e.g. sustained release gel, readily canbe prepared by employing 17β-estradiol in one of its relativelyinsoluble, long-acting forms, e.g. as estradiol cypionate.

Examples of the preparation of typical nasal compositions are set forthbelow. However, it is to be understood that these examples are given byway of illustration only and are not to be construed as limiting theinvention either in spirit or in scope as many modifications both inmaterials and in methods will be apparent to those skilled in the art.

EXAMPLE 1

25 milligrams of progesterone and 5 milligrams of 17β-estradiol werecombined with 10 milligrams of Tween 80. That mixture was then combinedwith a quantity of isotonic saline sufficient to bring the total volumeto 50 milliliters. The solution was sterilized by being passed through a0.2 micron Millipore filter.

EXAMPLE 2

50 milligrams of progesterone and 5 milligrams of 17 β-estradiol werecombined with 10 milligrams of Tween 80. That mixture was then combinedwith a quantity of isotonic saline sufficient to bring the total volumeof the solution to 50 milliliters. The solution was sterilized by beingpassed through a 0.2 micron Millipore filter.

EXAMPLE 3

250 milliliters of isotonic saline were heated to 80° C. and 1.50 gramsof Methocel were added, with stirring. The resultant mixture was allowedto stand at room temperature for 2 hours. Then, 50 milligrams ofprogesterone and 10 milligrams of 17β-estradiol were mixed together with10 milligrams of Tween 80. The steroid/Tween mixture and a quantity ofisotonic saline sufficient to bring the total volume to 500 milliliterswere added to the gel and thoroughly mixed.

EXAMPLE 4

Repetition of the procedure of Example 1, but omitting the 25 milligramsof progesterone, affords an "estrogen only" nasal composition.

EXAMPLE 5

Repetition of the procedure of Example 2, but omitting the 5 milligramsof 17β-estradiol, affords a "progesterone only" nasal composition.

EXAMPLE 6

Substitution of an equivalent quantity of estradiol benzoate, estradiolcypionate, estradiol dipropionate, estradiol enanthate or estradiol17-valerate for the 17β-estradiol employed in Example 1, 2, 3 or 4 andrepetition of the procedures there detailed affords other nasalcompositions according to the invention.

Naturally, the therapeutic dosage range for nasal administration of thecompositions of the present invention will vary with the size of thepatient, the condition for which the composition is administered and theparticular form of 17β-estradiol employed (when the composition is an"estrogen only" or estrogen/progestin combination). A typical dose of acombination form for use as a contraceptive would be from 10 μg to 500μg of 17β-estradiol and from 10 μg to 5000 μg of progesterone,administered nasally once daily. The quantity of nasal dosage formneeded to deliver the desired dose will of course depend on theconcentration of the active ingredients in the composition. For example,when a composition as described in Example 2 above is used to deliver atypical dose of 0.5 mg of progesterone, the volume of solution whichwould be needed would be approximately 0.5 ml.

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions and additions may be madewithout departing from the spirit thereof. Accordingly, it is intendedthat the scope of the present invention be limited solely by the scopeof the following claims.

What is claimed is:
 1. A method of mammalian contraception whichcomprises nasally administering to a female mammal a contraceptivelyeffective amount of a combination of progesterone and a pharmaceuticallyacceptable, estrogenically active form of 17β-estradiol.
 2. A method ofeliciting a progestational response in a mammal which comprises nasallyadministering thereto a progestationally effective amount ofprogesterone.
 3. A method of eliciting an estrogenic response in amammal which comprises nasally administering thereto an estrogenicallyeffective amount of a pharmaceutically acceptable, estrogenically activeform of 17β-estradiol.
 4. A method of mammalian contraception accordingto claim 1 which comprises nasally administering to a female mammal apharmaceutically acceptable nasal dosage form which comprises acontraceptively effective amount of a combination of progesterone and apharmaceutically acceptable, estrogenically active form of17β-estradiol, together with a nontoxic pharmaceutically acceptablenasal carrier therefor.
 5. A method according to claim 2 for eliciting aprogestational response in a mammal which comprises nasallyadministering thereto a pharmaceutically acceptable nasal dosage formwhich comprises a progestationally effective amount of progesterone anda nontoxic pharmaceutically acceptable nasal carrier therefor.
 6. Amethod according to claim 3 for eliciting an estrogenic response in amammal which comprises nasally administering thereto a pharmaceuticallyacceptable nasal dosage form which comprises an estrogenically effectiveamount of a pharmaceutically acceptable, estrogenically active form of17β-estradiol and a nontoxic pharmaceutically acceptable nasal carriertherefor.
 7. A method according to claim 1, 3, 4 or 6 wherein thepharmaceutically acceptable, estrogenically active form of 17β-estradiolis selected from the group consisting of 17β-estradiol, 3-monoesters of17β-estradiol, 17-monoesters of 17β-estradiol and 3,17-diesters of17β-estradiol.
 8. A method according to claim 7 wherein thepharmaceutically acceptable, estrogenically active form of 17β-estradiolis 17β-estradiol.
 9. A method according to claim 7 wherein thepharmaceutically acceptable, estrogenically active form of 17β-estradiolis estradiol benzoate.
 10. A method according to claim 7 wherein thepharmaceutically acceptable, estrogenically active form of 17β-estradiolis estradiol cypionate.
 11. A method according to claim 7 wherein thepharmaceutically acceptable, estrogenically active form of 17β-estradiolis estradiol dipropionate.
 12. A method according to claim 7 wherein thepharmaceutically acceptable, estrogenically active form of 17β-estradiolis estradiol enanthate.
 13. A method according to claim 7 wherein thepharmaceutically acceptable, estrogenically active form of 17β-estradiolis estradiol 17-valerate.
 14. A method according to claim 4, 5 or 6wherein said dosage form is a nasal solution.
 15. A method according toclaim 4, 5 or 6 wherein said dosage form is a nasal suspension.
 16. Amethod according to claim 4, 5 or 6 wherein said dosage form is a nasalointment.
 17. A method according to claim 4, 5 or 6 wherein said dosageform is a nasal gel.
 18. A method according to claim 4 or 6 wherein saiddosage form is a sustained release nasal dosage form.
 19. A methodaccording to claim 4 or 6 wherein said dosage form is a sustainedrelease nasal gel.
 20. A method according to claim 4, 5 or 6 whereinsaid dosage form is isotonic.